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Immunological and MRI Basics in Multiple Sclerosis

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Immunological and MRI Basics in Multiple Sclerosis Powered By Docstoc
					Immunological and MRI Basics in Multiple Sclerosis
Kathleen Costello, RN, MS,CRNP, MSCN University of Maryland Maryland Center for Multiple Sclerosis

What we know now……
Most common neurological disease of young adults Chronic disease of the CNS
Inflammation, demyelination, axonal degeneration

Approximately 350,000 cases in US 2/3 women Northern European ancestry Age of onset 15-55
Usually diagnosed in 20’s-30’s

Statistics
Worldwide distribution
High prevalence 30+/100,000
• • • • • Northern US and Canada (200/100,000) Most of Europe Southern Australia New Zealand Northeast Russia

Pathology
White matter lesions in CNS
Surrounded by plasma cells, immunoglobulins, macrophages, and lymphocytes

Inflammation Myelin injury and destruction Axonal injury and destruction

Demyelination and Axonal Transection

A

64m

B

45m

Reprinted with permission from Trapp BD et al. N Engl J Med. 1998;338:278-285. Copyright  1998 Massachusetts Medical Society. All rights reserved.

Disease Course
85% - 90% of patients present with a relapsing – remitting pattern (RR) of neurological symptoms 10% - 15% never have relapses (PP) After approx. 10 years nearly 50% of RR patients will show a progressive pattern to their disease. This percentage grows with time

Disease Courses in MS
Relapsing-remitting Secondary-progressive

Disability

Time

Disability Time

Primary-progressive

Progressive-relapsing

Disability

Time
Lublin FD et al. Neurology. 1996;46:907-911.

Disability Time

Natural History Over Time
Relapsing-remitting Primary-progressive Secondary-progressive Relapsing-remitting

15%

42%

85% Disease Type at Diagnosis

58% Disease Type at 11-15 Years After Diagnosis (Among Those With RRMS at Diagnosis)

Adapted from Weinshenker BG et al. Brain. 1989;112:133-146.

Symptoms
Fatigue Sensory disturbances Visual disturbances Elimination dysfunction Gait disturbances Spasticity Pain Tremor Cognitive

Symptoms vary widely in incidence and severity

Sources of Symptoms
Symptoms vary widely in incidence and severity
Cognitive loss Emotional disinhibition

Tremor, Ataxia

Optic neuritis Diplopia Vertigo Dysarthria INO Bladder dysfunction

Sensory symptoms, Lhermitte’s Pain Proprioception

MS: Prognosis
Gender: Women ; Men  Age of disease onset: <35 years ; >35 years  Monoregional ; polyregional  Complete recovery after exacerbation 
Poor recovery after exacerbation 

Brainstem symptoms (nystagmus, tremor, ataxia, dysarthria)  High incidence of attacks  High number of lesions on presenting MRI 

Diagnosis
History Neurological Exam Imaging - MRI Imaging - MRI LP EP’s Exclude other potential diagnoses

MRI in MS


MRI demonstrates approximately 90– 95% of white matter lesions in brain MRI demonstrates 50–75% lesions in spinal cord



Use of MRI
MRI is a useful tool in helping to make the diagnosis of MS MRI may also be helpful in clinical decision making Cost and availability are limiting factors in repeated MRI’s in the clinical setting

MRI Basics
MRI uses a strong magnetic field to align the hydrogen nuclei (protons) in the direction of the magnetic field A radio frequency electromagnetic pulse is then used to knock the protons off their axes, thus sending them out of alignment with the magnetic field

MRI Basics
The pulse is then stopped and the protons return to their alignment with the magnetic field This return to alignment is known as relaxation Different tissues “relax” at different rates, which gives the anatomic contrast seen with the MRI

T1 Weighted Images
The time it takes the protons to return to their original orientation, after the pulse stops is the longitudinal relaxation time or T1 Emphasizes the differences between the tissues, and shows excellent anatomic detail. Areas of abnormality show up dark on T1, therefore these images do not often demonstrate pathology best.

T1 Weighted Images

T1 with Gadolinium
Demonstrates breakdown of BBB Areas of active inflammation New lesions remain enhanced for brief time

T1 with Gadolinium

T1 Hypointensities
“Black Holes” Thought to be areas of axonal loss Can be “black holes” that are temporary with a new lesion Black holes not associated with a new lesion are thought to be areas of permanent damage

T1 Black Holes

T2 Weighted Images
The time it takes for the protons to dephase and for the signal to die away is known as Transverse relaxation time or T2 Relaxation time for T2 images are usually long Show contrast between normal and abnormal tissue better than T1 Abnormal increases in water content appear bright on T2

T2 Weighted Images

Conventional T2

FLAIR
Fluid Attenuated Inversion Recovery

FLAIR Image

FLAIR Image and T-1 Black Holes

MS Lesions on MRI
A B

T2
BOD

T2-FLAIR

T1 precontrast
black holes

C

D

T1/Gd postcontrast
disease activity

Spinal MRI in MS
Spinal cord lesions in 75% of MS patients Predominantly in C-spine Usually dorsolateral or central and 0.5 cm by 1-2 cm, and 1-2 vertebral segments. Less likely to enhance or cause cord swelling More likely to cause progressive disease T2 less predictive of disability than atrophy

Cord Lesion

Brain Atrophy
Cerebral atrophy is a global measure of disease which measures irreversible tissue damage Serial measures may reflect disease progression “Potentially” the most valid MRI surrogate marker May be “faster, simpler, and better” than current measures (Jagust and Noseworthy. Neurology. 2000;54:782)

Examples of BPF in MS

31 yo male Healthy control BPF 0.87 z-score = 0

36 yo woman RR MS (2 yrs) BPF 0.85 z-score = -2.6

43 yo woman SP MS (19 yrs) BPF 0.71 z-score = -20.8

McDonald Diagnostic Criteria
Preserve traditional diagnostic criteria of 2 attacks of disease separated in space and time
Must be no better explanation Add specific MRI criteria, CSF findings, and analysis of evoked potentials as means of identifying the second “attack”
McDonald WI et al. Ann Neurol. 2001;50:121-127.

MacDonald Diagnostic Criteria
Conclude that the outcome of the diagnostic workup should yield 1 of 3 outcomes:
MS Possible MS Not MS

New criteria utilize MRI, CSF or evoked potential testing when only one lesion found and/or only one attack or when onset is insidious neurological progression

MRI Evidence of Dissemination in Time
A Gd-enhancing lesion demonstrated in a scan done at least 3 months following onset of clinical attack at a site different from attack In absence of Gd-enhancing lesions at 3 mo scan, follow-up scan after an additional 3 months showing Gd-lesion or new T-2 lesion

McDonald MRI Criteria
Abnormal MRI consistent with MS defined as:
Must have at least 3 of the following:
• 1Gd-enhancing lesion or 9 hyperintense lesions if no Gd-enhancing lesion • 1 or more infratentorial lesions • 1 or more juxtacortical lesions • 3 or more periventricular lesion
– 1 cord lesion = 1 brain lesion

McDonald MRI Criteria

Gd-enhancing

T2-hyperintense

Infratentorial

Juxtacortical

Periventricular

Spinal Cord

Application of New Diagnostic Criteria
T2 3 months

Gd

Proposed diagnostic criteria
An effort to expedite diagnosis Have become part of inclusion/exclusion for newer clinical trials Makes an effort to define clinically isolated syndrome to enable earliest treatment

MRI Techniques
Conventional Research

• T2 (lesion burden)
• FLAIR (lesion burden) • T1 (atrophy) • T1 + Gd (active lesions)

• 3x Gd (active lesions)
• MTR (tissue damage) • Spectroscopy (more sensitive for axonal damage) • BPF (atrophy)

Natural History of MS
Measures of brain volume Relapses and impairment MRI burden of disease MRI activity Preclinical Relapsing-remitting Secondary-progressive

Time
Adapted from DE Goodkin, MD. UCSF MS Curriculum. January 1999.

Immune mediated Disease
Inflammation Demyelination Axonal degeneration and loss Must be knowledgeable about the normal immune system and the dysregulation in MS

Immunological Basis of MS

Immunological Basis for MS Normal Immune System
Protects from pathogens such as
Bacteria Viruses Parasites Fungi

Protects through
Innate immunity Adaptive immunity

The Immune System
Innate immunity
Pathogen

Macrophage

Immunity to certain pathogens that is common to all healthy individuals Does not require prior exposure to the pathogen Immediate destruction of some pathogens by phagocytic cells, such as macrophages and neutrophils, and NK cells

The Immune System
Adaptive immunity
Requires exposure to pathogen to stimulate immune system response Cellular immunity Humoral immunity
• • • •
• Cytotoxic T-cells (CD 8) • TH1 cells (CD 4)

TH2 cells (CD 4) B lymphocytes Antibodies Activation of complement

The Immune System
B-cells recognize antigen that is present outside of cells in its natural state T-cells detect antigen generated inside host cells and presented on the cell surface Both B-cells and T-cells must receive an additional (co-stimulatory) signal in order to be activated

Humoral Immunity
B-cells have specific antibodies on their surface

They circulate looking for an recognizable antigen
Under the influence of cytokines released from Th-2 cells, B-cells give rise to plasma cells that secrete large amounts of antibodies Plasma cells do not leave the lymphoid tissue

Humoral Immunity
Antibodies work by
Neutralization
• Binding to pathogens and blocking the path to body cells

Opsonization
• Enabling phagocytic cells to recognize pathogens by coating the pathogen

Complement
• Some antibodies activate a series of proteins called complement that have been circulating, inactive in the blood. Complement and the antibody combine in a partnership that can react to an antigen and help to destroy it.

B-cells give rise to plasma cells, that are antibody producing factories

Cellular Immunity
T-lymphocytes each have cell surface receptors
Distinct from lymphocyte to lymphocyte This enables lymphocytes to recognize a wide variety of antigens

Cellular Immunity
Once a T-cell is activated by antigen presentation:
It proliferates in a process known as clonal expansion These activated cells produce cytokines that can activate the “killer” mechanism of macrophages Antigen specific lymphocytes undergo apoptosis once the antigen is removed Some antigen specific lymphocytes persist and are the basis for immunological memory

Cellular Immunity
The cells that present antigen to T-cells are antigen presenting cells
Dendritic cells Macrophages B-cells

These cells display antigen protein particles on specialized cell surface molecules known as MHC

Cellular Immunity
2 classes of MHC molecules
MHC I MHC II

MHC I are recognized by cytotoxic T-cells (CD 8) MHC II are expressed on the surface of macrophages or B-cells and are recognized by TH1 or TH2 cells (CD 4)

Cellular Immunity
Virus

APC processing Virus
Co-stimulatory molecules

Activated Th-1 or Th-2

Activated Th-1or Th-2

APC (Macrophage) MHC II

Resting T cell T-cell Receptor

Activated Th-1 or Th-2

Presentation of Virus protein To Resting Th-1 Cell

Activated Th-1 or Th-2

CD 4 Cell Cytokine Production
TH1 cells-activate macrophages and produce:
IFN- TNF- IL-2 LT (lymphotoxin)

TH2 cells-activate B-cells and produce:
IL-4 IL-5 IL-10 (regulatory cytokine) IL-13 TGF 

Immune Dysregulation
T-cells that recognize self-antigen are generally deleted in the thymus May be a small # of auto-reactive cells still present In autoimmune illness, the regulatory mechanisms that keep these T-cells in check are not working properly Without regulation, auto-reactive T-cells can proliferate

Immune Dysregulation
Molecular mimicry
Self protein is structurally similar to nonself antigen T-cells can recognize self-antigens if they bear enough similarity to the nonself antigen

Immune System in Multiple Sclerosis
TH1 cells are stimulated in the periphery by presentation with antigen
eg, a virus particle

Once activated
They proliferate They release cytokines and metalloproteinases that break down the extracellular matrix of the BBB

Multiple Sclerosis
Once in the CNS, TH1 cells
Are presented with a myelin protein The myelin protein is similar to the antigen presented in the periphery Become reactivated Release damaging cytokines Interferon-gamma, TNF-beta, IL-2 B-cell activity stimulated, antibody production and complement activation

MS Immune Response
MMP

Microglial Cell

APC
Myelin Protein

Co-stimulatory Molecules

Activated TH-1

APC TCR

TH-1

Activated TH-1

Activated TH-1

TH-1 IL-2

MHC-II

Antigen

Activated TH-1

LFA-1 ICAM

TNF-α

Ifn-γ

Periphery

MMP

B-cell

CNS

MS Immune Response
BBB
MMP

APC

Activated TH-1 Activated TH-1 APC

TH-1

Activated TH-1
MMP

TH-1 IL-2

TNF-α
Activated TH-1

Ifn-γ

MMP

Periphery

CNS

B-cell

Inflammation/demyelination/and axonal damage and MRI

Inflammation in the CNS = Gd Enhancement
APC
(Microglia)

TH-1 IL-2 TNF-α Ifn-γ

B-cell

Pathology of MRI Gd-Enhancing lesion

Perivascular Inflammation
Dhib-Jalbut, S.

Gd-Enhancing Lesions

Demyelination in MS

Axonal Loss in MS

Results of autoimmune activity within the CNS
Neurological symptoms followed by some degree of recovery Relapses and remissions Little axonal injury or damage Permanent damage within the CNS Progression Axonal damage and loss

Interferon Beta
Inhibits synthesis of inflammatory cytokines
IFN-gamma, TNF-alpha

Downregulates expression of MHC class II molecules induced by IFN-gamma Reduces antigen presentation to T-cells Inhibits T-cell proliferation Downregulates adhesion molecules and promotes BBB integrity

Ifn β effect on MS Immune Response
BBB
APC
Activated TH-1

Ifn β
Antigen

Myelin Protein

APC TCR MHC-II

TH-1

Activated TH-1

Activated TH-1

TH-1 IL-2 TNF-α

Ifn β

Activated TH-1

Ifn-γ

Periphery

Ifn β

CNS

Glatiramer Acetate
Induces suppressor T-cells Structurally similar to myelin basic protein and when glatiramer induced T-cells are presented with MBP in the CNS, they are stimulated to proliferate and release cytokines
TGF-beta, IL-4, IL-10

These T-cells are thought to suppress proinflammatory T-cells in a process called bystander supression

GA Induced Immune Response
BBB
APC
Activated TH-2

Copaxone Antigen

Myelin Protein

APC

TH-0 TH-2

Activated TH-2

Activated TH-2

TH-2

TCR
MHC-II
Glatiramer Induced T-cell

IL-10 IL-4
Activated TH-2 Bystander suppression on other T-cells

IL-6

Periphery

CNS

BBB

Research in MS
BMS-block costimulatory
APC Activated TH-1

MMP

APC

Activated TH-1

TH-1
Anti-IL12

Activated TH-1
MMP

TH-1 IL2

TNF-α

Campath

Activated TH-1 Antegren
MMP

Ifn-γ

Summary
Nurses Role:
Education Advocacy Support

Understanding of the disease:
Immune basis Clinical features/diagnosis MRI

And through our understanding of MS treatments, symptomatic management, our role, current issues and current research


				
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